Triple negative breast cancer (TNBC) represents an aggressive tumor type with a distinct lack of effective treatment options. Standard-of-care chemotherapy regimens typically produce a partial response followed by regression months to years later. This Phase I application tests the hypothesis that, in subtypes of TNBC, activation of the WNT pathway represents the underlying mechanism of resistance to chemotherapy. Subsets of TNBC patients demonstrate high levels of LRP6, which correlates with activated WNT signaling and poor prognosis. Over the past 10 years, a clear link has been established between breast cancer stem cells and activated WNT signaling. Cells that are not affected by chemotherapy often exhibit activated WNT signaling. However, the distinct lack of effective WNT inhibitors has slowed the translation of these discoveries into patients. No WNT inhibitors are available in the clinic. We have developed a monoclonal antibody that targets LRP6, a co-receptor in the canonical WNT pathway. The initial mouse IgG antibody (SST-102mAb) demonstrates significant in vitro and in vivo activity to inhibit the WNT pathway. Based on these studies, in order to facilitate clinical development, we have developed a human chimeric version (SST-112mAb) that potently inhibits WNT signaling in a TNBC cell line. SST-112mAb targets the hinge region of the extracellular domain of LRP6, which is unique from other approaches by pharma/biotech to target LRP6. Additionally, SST-112mAb specifically targets canonical WNT activation unlike other pan-WNT inhibitors currently in early clinical trials. This SBIR Phase I application proposal is designed to initially evaluate SST-112mAb's in vitro potency in inhibiting the growth of TNBC cell lines with elevated LRP6 as well assess SST-112mAb's efficacy in established cancer stem cell assays. We will perform subsequent studies to evaluate SST-112mAb's in vivo efficacy as monotherapy and in combination with standard-of-care drugs currently used for treating TNBC. Targeted biologics have the distinct advantage of exhibiting specificity for the target while minimizing off-target toxicities. Our overall goal and development approach uses an established model for a streamlined progression through to clinical trials. Successful completion of these Phase I aims represents critical steps toward those goals.